Molecular Pharmacology, Vol 11, 450-461, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Studies on Three Microsomal Electron Transfer Enzyme Systems

Effects of Alteration of Component Enzyme Levels in Vivo and in Vitro

¹ Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Liver microsomes contain three multicomponent enzyme systems that appear to share the same pyridine nucleotide-linked electron input enzymes. They are the mixed-function oxidase, the fatty acyl-CoA desaturate, and the lipid peroxidase. The three electron transfer pathways can be considered alternate pathways of lipid metabolism, but they also metabolize xenobiotics. Deprivation of food, a high-carbohydrate, low-fat diet, and phenobarbital administration have differential effects on the three pathways. The highcarbohydrate diet causes large increases in desaturase content, cessation of peroxidase activity, and a considerable decrease in mixed-function oxidase activity. Induction of mixed-function oxidase activity by phenobarbital markedly lowers desaturase activity but does not affect the peroxidase. Fasting causes an increase in the lipid peroxidase and reduces the desaturase activity but does not affect the level of mixed-function oxidase. These changes are accompanied by modifications of electron transfer component (FP_D, FP_T, and cytochrome b₅) levels, but no systematic relationship emerges. Similarly, alterations of the activities of these electron transfer pathways in vitro by fortification of microsomes with FP_D or cytochrome b₅ reveals no consistent relationship: e.g., fatty acyl-CoA desaturase is increased, mixed-function oxidase activity is inhibited, and lipid peroxidase activity is unaffected by fortification of microsomes with cytochrome b₅. These results suggest that rate limitation and electron flow direction are determined at the level of the individual terminal enzymes.